CD4+ T cells are important in regulating immunity to pathogens, allergic responses, asthma, and immunity to self or tumor tissues (Zhu et al., 2010 Annu. Rev. Immunol. 28:445-489; Muranski et al., 2009 N. P. Restifo, Curr. Opin. Immunol. 21:200-208; Zhu et al., 2008 Blood 112:1557-1569). Depending on the microenvironmental cues present, naïve CD4+ T cells may differentiate into one of several T helper (TH) cell lineages, including TH1, TH2, Th17, TH22, and regulatory T (Treg) cells (O'Shea et al., 2010 Science 327:1098-1102; Murphy et al., 2010 Nat. Immunol. 11:674-680). TH1 and TH2 cells are effector cells that express T-bet and GATA-3, respectively (Zhu et al., 2010 Annu. Rev. Immunol. 28:445-489). In contrast, Treg cells suppress effector T cell functions and are essential for regulating autoimmune responses (Tang et al., 2006 Immunol. Rev. 212:217-237), and the recently described TH22 cells secrete interleukin-22 (IL-22) and might be a subset of skin-homing cells responsible for inflammation (Duhen et al., 2009 Nat. Immunol. 10:857-863; Trifari et al., 2009 Nat. Immunol. 10:864-871). Th17 cells augment host defense, have a major role in mucosal immunity, enhance a number of autoimmune diseases, and release cytokines, including IL-17A and IL-17F (Korn et al., 2009 Annu. Rev. Immunol. 27:485-517). The contribution of Th17 cells to tumor immunity varies, showing the potential for both antitumorigenic and protumorigenic activity (Zou et al., 2010 Nat. Rev. Immunol. 10:248-256). Therefore, identification of the mechanisms that control Th17 responses is essential to understand tumor immunity. The functions of cytokines (for example, transforming growth factor-β (TGF-β), IL-6, IL-1b, IL-21, and IL-23) and transcription factors (such as RORC2 and RORa) in human Th17 cell development are distinct from TH1 and TH2 effector cells (Zhou et al., 2009 Curr. Opin. Immunol. 21:146-152; Manel et al., 2008 Nat. Immunol. 9:641-649; Yang et al., 2008 Nature 454:350-352; Volpe et al., 2008 Nat. Immunol. 9:650-657). Further, natural agonists for the aryl hydrocarbon receptor (AHR) augment murine Th17 cell differentiation (Veldhoen et al., 2009 J. Exp. Med. 206:43-49). However, the specific costimulatory pathways that may influence Th17 generation and stability remain to be elucidated.
Antigen-specific and antigen-nonspecific costimulatory signals from antigen-presenting cells (APCs) are necessary for the activation, differentiation, and function of T lymphocytes (Greenwald et al., 2005 Annu. Rev. Immunol. 23:515-548). CD28 is considered to be the primary co-signaling molecule on CD4+ T cells because of its early expression, and it is often used to generate IL-17-producing lymphocytes (Manel et al., 2008 Nat. Immunol. 9:641-649; Yang et al., 2008 Nature 454:350-352; Volpe et al., 2008 Nat. Immunol. 9:650-657; Acosta-Rodriguez et al., 2007 Nat. Immunol. 8:942-949; Acosta-Rodriguez et al., 2007 Nat. Immunol. 8:639-646; Wilson et al., 2007 Nat. Immunol. 8:950-957). However, in addition to CD28, signaling via the inducible costimulator (ICOS, also called CD278) is required for optimal cytokine secretion, because both molecules are essential for optimal IL-17A secretion by murine Th17 cells (Park et al., 2005 Nat. Immunol. 6:1133-1141). Recent findings in murine models have revealed that ICOS amplifies Th17 responses by inducing the expression of the transcription factor c-MAF and therefore transactivating IL-21 production (Bauquet et al., 2009 Nat, Immunol. 10:167-175).
Although both CD28 and ICOS are important for the generation of murine Th17 cells, their particular roles in regulating key genes in human Th17 cells remain to be identified. The present invention satisfies this need in the art.